It has been reported that 1.alpha.-hydroxy-vitamin D.sub.3 has a physiological activity, mainly in the transport of calcium to the bones; Omdahl et al., Physiol. Rev. 53. 327 (1973).
It is known to convert cholesterol to 1.alpha.,2.alpha.-epoxycholesta-4,6-dien-3-one (I) and to treat this latter with lithium metal in liquid ammonia, resulting in the production of 1.alpha.,3.beta.-dihydroxycholest-5-ene (V), which is also a precursor of 1.alpha.-hydroxy-vitamin D.sub.3 ; Barton et al., J.A.C.S. 95, 2748 (1973).
The process of the present invention starts with the same epoxy derivative (I), and is treated with lithium and ammonium chloride in liquid ammonia, but under different conditions of reaction, so as to result mainly in the novel 1.alpha.,3.beta.-dihydrocholest-6-ene (II), which is converted to the corresponding 1.alpha.,3.beta.-dialkanoyloxy-cholest-6-ene (III); the latter is brominated to yield 1.alpha.,3.beta.-dialkanoyloxy-6.beta.,7.alpha.-dibromocholestane (IV) which is reacted with an anhydrous base to give the di(alkanoyloxy) derivative of 1.alpha.-hydroxy provitamin D.sub.3, which can be converted to 1.alpha.-hydroxy provitamin D.sub.3 or 1.alpha.-hydroxy vitamin D.sub.3.
According to another route, the process of the invention comprises oxidizing compound III to the corresponding 7-keto derivatve VII, which is reacted with toluene sulfonyl hydrazone to yield the corresponding 7-toluene sulfonyl hydrazone (VIII) which upon heating with lithium hydride gives the desired 1.alpha.-hydroxy provitamin D.sub.3.
The novel compounds of the formulas II and III are; ##SPC1##
those of formulas IV and VII are; ##SPC2##
while those of formulas I and VI are: ##SPC3##
wherein R designates lower alkanoyl.
The process of the present invention comprises treating 1.alpha.,2.alpha.-epoxy-cholesta-4,6-dien-3-one (I), dissolved in a suitable solvent at a low temperature (of about -30.degree.C) with liquid ammonia, followed with a repeated treatment with ammonium chloride followed by lithium metal. Suitable solvents are ethers, such as tetrahydrofuran. Advantageously there is used an excess of ammonium chloride, and this is followed by an excess of lithium. This is repeated a number of times, usually between 4 and 7 times. The main product of this process step is the production of 1.alpha.,3.beta.-dihydroxycholest-6-ene (II) which is obtained in a yield of about 50 percent. Byproducts are cholesterol and the known 1.alpha.,3.beta.-dihydroxycholest-5-ene.
1.alpha.,3.beta.-dihydroxycholest-6-ene is converted to the corresponding 1.alpha.,3.beta.-di(lower alkanoyl)-derivative III, which is reacted with bromine to give the dibromo-derivative IV, which latter is dehydrobrominated by treatment with a suitable base, such as an alkylated pyridine, dimethyl formamide, hexamethylphosphoramide or the like. The preferred embodiment comprises heating the reactant IV with hexamethylphosphoramide for a number of hours at a temperature of about 100.degree.C to about 140.degree.C, in the presence of a small quantity of tetraalkyl ammonium salts of a dialkyl phosphate or with similar salts of an alkyl phosphonate. The latter results in a yield of about 50 percent of the desired 1.alpha.-hydroxy provitamin D.sub.3. The conversion of the latter to 1.alpha.-hydroxy vitamin D.sub.3 has been described previously.
A modification of the process of the present invention takes a different route, starting with compound III. The 1.alpha.,3.beta.-(di-lower alkanoyl)cholest-6-ene in a solvent like tert-butanol is treated with mercuric bromide and sodium acetate and irradiated at room temperature at a wavelength of about 254 nm, during about 5 hours. After filtration and extraction with a solvent like hexane, there is obtained 1.alpha.,3.beta.-dihydroxycholest-5-en-7-one-di(lower alkanoyl) derivative VII. The latter is dissolved in a solvent like methanol, treated with p-toluenesulfonylhydrazine and heated during about 5 hours under an inert gas, such as nitrogen. The solvents were removed under reduced pressure and the residue was dissolved in methylene chloride and subjected to chromatography on alumina to give the p-toluene-sulfonylhydrazone derivative VIII, which was dissolved in dry toluene and treated with lithium hydride. After refluxing under nitrogen the reaction mixture is cooled, filtered, and the precipitate was washed with ether. The combined organic fractions were washed with dilute aqueous sulfuric acid, with water, and evaporated, resulting in 1.alpha.,3.beta.-(di-lower alkanoyl)-cholest-5,7-diene.
The preferred intermediate if the formula III is the 1.alpha.,3.beta.-diacetate.
Due to its physiological properties, 1.alpha.-hydroxy provitamin D.sub.3 and 1.alpha.-hydroxy vitamin D.sub.3, obtained from the provitamin are valuable additives to foodstuffs for human and for animal use. They can be used in vitamin preparations of various kinds, and are especially useful as ingredients in multivitamins.